Norepinephrine plays an important role in modulating adrenergic neurotransmission in the brain as well as in the heart. Norepinephrine transporters (NET), located presynaptically, regulate the adrenergic signals by re-uptake of norepinephrine from the synaptic cleft. They are target sites for many widely prescribed antidepressants, such as desipramine, reboxetine, atomoxetine and valenfaxine, which show high potency in blocking the norepinephrine reuptake. Imaging of norepinephrine neurons by I-131/ I-123 is commonly used for diagnosis and treatment of pheochromocytoma and neuroblastoma expressing NET and the same tracer is also useful for imaging norepinephrine neuronal function in myocardial infarct and cardiomyopathy. However, no NET-specific tracer has been successfully developed for measuring the location and density of NET in the living human brain by single photon emission computed tomography (SPECT) and positron emission tomography (PET). There is a compelling need to develop NET-specific imaging agents to add clinical diagnosis and monitor drug treatment. Based on the chemical structure of 2-iodo-(R)-nisoxetine, a highly specific ligand of NET, Kd = 0.05 nM, its derivatives are proposed. These new agents may provide useful tools to study NET in normal and disease states. The specific aims of this project are: 1. Synthesize a series of phenoxy-3- phenylpropaneamine derivatives and precursors for radio labeling. 2. Perform in vitro monoamine transporter binding studies and monoamine transporter cell uptake competition studies. Structure activity relationship of NET binding properties will be evaluated. 3. Study radiochemistry in preparing I-123, I-124 and F-18 labeled agents (at a tracer level). 4. Evaluate biodistribution in rats. 5. Perform in vivo imaging studies in baboons, including in vivo metabolism and kinetic modeling studies. Ultimately, we hope to identify at least two final drug candidates (one I-123/I-124 and one F-18 agents) for further pre-clinical development. The proposed new NET imaging agents will be useful for diagnosis and monitoring NET binding sites involved in many antidepressants and medications developed for treatment of attention deficit/hyperactivity disorder (ADHD).